Particle generation using microfluidic systems—even chip-based systems—is not new in and of itself. While nanoparticles in particular appear to have been the subject of much published work in this area (S. Desportes, Z. Yatabe, S. Baumlin, V. Genot, J.-P. Lefevre, H. Ushiki, J. A. Delaire, R. B. Pansu, “Fluorescence lifetime imaging microscopy for in situ observation of the nanocrystallization of rubrene in a microfluidic set-up”, Chemical Physics Letters, 2007, v.446: pp. 212-216; S. Pabit and J. Hagen, “Laminar-Flow Fluid Mixer for Fast Fluorescence Kinetics Studies”, Biophysical Journal, 2002, v.83: pp. 2872-2878; H. Nagasawa, T. Tsujiuchi, T. Maki, and K. Mae, “Controlling fine particle formation processes using a concentric microreactor”, America Institute of Chemical Engineers Journal, 2007, v.21(no. 1): pp. 196-206, 2007; T. L. Sounart, P. A. Safier, J. A. Voigt, J. Hoyt, D. R. Tallant, C. M. Matzke, and T. A. Michalske, “Spatially-resolved analysis of nanoparticle nucleation and growth in a microfluidic reactor”, Lab-on-a-Chip, 2007, v.1: pp. 908-915) treatment of micron-sized and larger particles appears to be lacking, presumably due to the difficulties posed by clogging and surface nucleation. Moreover, these prior art examples typically rely on coaxial capillary arrangements external to the microfluidic chip (cf. S. Pabit, op. cit., and H. Nagasawa, op. cit.) or involve irregular flow patterns with chimney-like (H. Klank, G. Goranovic, J. P. Kutter, H. Gjelstrup, J. Michelsen, and C. H. Westergaard, “Ply measurements in a microfluidic 3D-sheathing structure with three-dimensional flow behavior,” Journal of Micromechanics and Microengineering, 2002, v.12: pp. 862-869) or piecewise-focused geometries (X. L. Mao, J. R. Waldeisen, and T. J. Huang, “‘Microfluidic drifting’—implementing three-dimensional hydrodynamic focusing with a single-layer planar microfluidic device,” Lab-on-a-Chip, 2007, v.2: pp. 1260-1262) poorly suited to uniform particle nucleation and growth.
Microreactors are particularly beneficial for reaction experiments or particle production processes in which either reactants or products are explosive, radioactive, acutely hazardous, extremely costly, particularly rare, or available in only very limited quantities (e.g., materials collected in forensic analysis, etc.) because small quantities of reagents are used and small quantities of waste are generated. Moreover, because reactions occur in an essentially closed system, these techniques may also be particularly applicable or adaptable for work with reagents and products which are reactive to atmospheric air, moisture, etc. Non-aqueous chemistries, organic chemistries, ionic liquid chemistries, etc., may all be adaptable to these reaction schemes.
Microreactors fabricated on-chip using techniques typical of micromachining or lithographic techniques like those employed for the fabrication of integrated circuits, microelectromechanical systems (MEMS), and lab-on-a-chip systems offer a number of advantages over comparable off-chip designs. While similar phenomena and geometries can be achieved in capillary-based systems, blown-glass assemblies, and devices produced by conventional small-scale machining, such systems typically lack the dimensional consistency and economies of scale made possible by the parallelized nature of microfabrication. Moreover, discretely fabricated components can prove problematic to integrate effectively, whereas multiple functionalities can be readily incorporated onto a single chip or micromachined substrate. As such, integrated on-chip designs avoid problems of component interconnection, minimize required sample amounts, decrease dead volumes and transport volumes, reduce sample dispersion, and minimize the number of discrete parts and connections which can potentially fail, clog, or leak.
Continuous, flow-through microfluidic chemical reactors, i.e., microreactors, offer a number of potential benefits over more conventional large-scale and batch processes for the production of particles (nanocrystals, nanoparticles, quantum dots, microparticles, etc.). Specifically, the ability to conduct reactions at scales comparable to the diffusion length with precise control over flow geometry and reaction conditions makes it possible to avoid significant deviations in microenvironment and residence times, which can occur in larger systems. Moreover, as will be shown below, the option to serially engage these microreactors makes it possible to effectively decouple and independently control the processes of nucleation, growth, and particle aggregation while offering options for integrating additional functionalities downstream such as particle sorting or separation, solvent or solute extraction, spectroscopic or light scattering analysis, thermal treatment, surface functionalization, etc.
For the purposes of particle generation, 2-dimensional focusing (or in fact any simple two-dimensional 2- or 3-stream laminar mixing) is less than ideal for two reasons. First, the planar (reacting) interface between the streams contacts the channel wall (i.e., floor and ceiling), tending to result in surface crystal nucleation that can lead a loss of particle uniformity or even clogging. Second, the parabolic velocity profile typical of pressure driven flow in a channel means that particles nucleating at different positions along the planar mixing interface will experience different velocities, residence times, and growth histories, tending to broaden the size distribution of resulting crystals. Alternatives which have previously been explored to improve residence time uniformity include a variety of rapid mixing schemes (S. Hardt, K. S. Drese, V. Hessel, and F. Schonfeld, “Passive micromixers for applications in the microreactor and μTAS fields,” Microfluidics and Nanofluidics, 2005, v.1: pp. 108-118) and a suggestion of relying on Taylor dispersion (lateral diffusion) to “average-out” residence times in slow moving flows (S. Krishnadasan, J. Tovilla, R. Vilar, A. J. deMello, and J. C. deMello, “On-line analysis of CdSe nanoparticle formation in a continuous flow chip-based microreactor”, Journal of Materials Chemistry, 2004, v.14: pp. 2655-2660). Most mixing schemes presented suffer the aforementioned wall nucleation problems, limiting their usefulness for particle production. While the Taylor dispersion concept may work serviceably for nanoparticle production, larger particles will not have the same degree of lateral mobility, and will tend to settle out of the flow at the low velocities required for this approach to work.
Achieving highly symmetrical three-dimensionally-focusable coaxial core/sheath flows on-chip has proven to be a significant challenge due to the largely planar, two-dimensional nature of typical chip fabrication techniques. While the prior art provides examples of coaxial and three-dimensional flow focusing devices, they are generally designed with little concern for end-to-end core/sheath interface uniformity or surface interactions. One of the most common approaches to producing on-chip three-dimensionally focused and/or coaxial flow is the use of piecewise focusing, where the core flow is focused first in the lateral dimension by one sheath flow, then in the vertical direction by another sheath flow, or vice versa (G. Hairer, G. S. Parr, P. Svasek, A. Jachimowicz, and M. J. Vellekoop, “Investigations of micrometer sample stream profiles in a three dimensional hydrodynamic focusing device,” Sensors and Actuators B, 2008, v.132: pp. 518-524; R. Scott, P. Sethu, and C. K. Harnett, “Three dimensional hydrodynamic focusing in a microfluidic Coulter counter,” Review of Scientific Instruments. 2008, v.79: pp. 046104; X. L. Mao, J. R. Waldeisen, and T. J. Huang, (op. cit.); C.-C. Chang, Z.-X. Huang, and R-J Yang, “Three-dimensional hydrodynamic focusing in two-layer polydimethylsiloxane (PDMS) microchannels,” Journal of Micromechanics and Microengineering, 2007, v.11: pp. 1479-1486). Unfortunately, piecewise focusing of reacting flows guarantees non-uniformity by providing not one but two sequential reacting interfaces. In two of these examples, three-dimensional focusing is further accomplished by forcing the core or sample stream against a wall of the system, producing a non-coaxial flow unsuitable for particle production due to the potential for surface nucleation and clogging (cf. Hairer, op. cit. and R. Scott, op. cit.). Chimney-like geometries have also been presented in which the core flow is introduced from the out-of-plane direction into a substantially two dimensional fluidic system, again yielding a significantly non-uniform reacting interface with distinct upstream and downstream microenvironments near the injection point (H. Klank, G. Goranovic, J. P. Kutter, H. Gjelstrup, J. Michelsen, and C. H. Westergaard, (op. cit.); A. Wolff, I. R. Perch-Nielsen, U. D. Larsen, P. Friis, G. Goranovic, C. R. Poulsen, J. P. Kutter, and P. Telleman, “Integrating advanced functionality in microfabricated high-throughput fluorescent-activated cell sorter,” Lab-on-a-chip, 2003, v.3: pp. 22-27). Even more complex device geometries have been suggested, likely to yield even more broadly distributed reaction conditions if applied to the problem of particle generation (N. Sundararajan, M. S. Pio, L. P. Lee, and A. A. Berlin, “Three-dimensional hydrodynamic focusing in polydimethylsiloxane (PDMS) microchannels,” Journal of Microelectromechanical Systems, 2004, v.13: pp. 559-567).
One of the more uniform coaxial flow geometries suggested for particle generation relies on a pulled capillary sandwiched between a blank coverslip and a molded polydimethylsiloxane (PDMS) layer patterned with microchannels (cf. S. Desportes, op. cit.). While the geometry of this device produces a uniform coaxial flow, the use of the soft PDMS elastomer makes the device more a disposable laboratory prototype than a true, durable, chip-based system. Many resort to PDMS and laminated PDMS structures to address the aforementioned difficulties of producing three-dimensional fluid flows with largely two-dimensional fabrication techniques (cf. R. Scott, op. cit.; C. C. Chang, op. cit.; and N. Sundararajan, op. cit.). The use of PDMS appears primarily to address the need to fabricate a channel of sufficient size to accommodate the capillary tube. The disadvantages of PDMS as an engineering material for micro fluidic systems are numerous and significant: lack of mechanical and dimensional stability, surface chemistry and reactivity, tendency to attract hydrophobic contaminants or particles, shrinkage or swelling due to absorption or interactions with common working fluids and reagents, and poor optical properties rendering PDMS-based systems unsuitable for many applications involving optical diagnostics.